Is it safe to use pregabalin (Lyrica) and gabapentin (Neurontin) together?

Using Pregabalin Together with Gabapentin

The combined use of pregabalin (Lyrica) and gabapentin (Neurontin) is not recommended due to increased risk of adverse effects without additional therapeutic benefit, as both medications work through the same mechanism of action at the α2δ subunit of voltage-gated calcium channels.

Mechanism and Pharmacological Overlap

Both pregabalin and gabapentin:

• Bind to the α2δ subunit of voltage-gated calcium channels 1
• Inhibit neurotransmitter release in the central nervous system 1
• Are primarily used for neuropathic pain conditions 1

Despite their similar chemical structures, they have important pharmacokinetic differences:

• Pregabalin has linear pharmacokinetics with higher bioavailability (≥90%) 2
• Gabapentin has nonlinear (saturable) absorption with bioavailability decreasing from 60% to 33% as dosage increases 2
• Pregabalin reaches peak plasma concentration faster (1 hour) compared to gabapentin (3-4 hours) 2

Safety Concerns with Combined Use

The combined use presents several significant concerns:

1. Additive adverse effects: Both medications can cause:

   • Dizziness
   • Somnolence
   • Peripheral edema
   • Fatigue
   • Ataxia 3

2. Lack of additional benefit: Clinical guidelines do not recommend combining these medications as they target the same mechanism of action 1

3. Risk of misuse: Both medications have potential for misuse, particularly in patients with history of substance abuse, and combining them may increase this risk 4

4. Pharmacokinetic interaction: While a formal drug interaction study showed "gabapentin pharmacokinetics following single- and multiple-dose administration were unaltered by pregabalin coadministration" 5, the clinical significance of combined use remains concerning due to additive pharmacodynamic effects.

Evidence from Case Reports

A case report documented adverse effects including drowsiness, dizziness, fatigue, and ataxia in a patient with diabetic neuropathy who was prescribed both medications concurrently. These symptoms resolved after discontinuation of pregabalin and adjustment of gabapentin dosage 3.

Alternative Approaches

For patients with inadequate pain relief on monotherapy, guidelines recommend:

1. Optimizing single-agent therapy first: Ensure adequate dosing of either pregabalin or gabapentin before considering alternatives 1

   • Gabapentin: Titrate up to 3600 mg/day in divided doses
   • Pregabalin: Titrate up to 600 mg/day in divided doses

2. Consider alternative first-line options if gabapentinoid monotherapy is inadequate 1:

   • Secondary-amine tricyclic antidepressants (nortriptyline, desipramine)
   • SNRIs (duloxetine, venlafaxine)
   • Topical lidocaine (for localized neuropathic pain)

3. Add a medication with a different mechanism of action rather than combining two gabapentinoids 1

Practical Recommendations

If a patient is currently taking both medications:

• Identify which medication provides better symptom control
• Gradually discontinue one medication while optimizing the dosage of the other
• Monitor for withdrawal symptoms, which may require slower tapering
• Consider renal function when determining appropriate dosing, as both medications require dose adjustment in renal impairment 5

For patients with refractory neuropathic pain not responding to a single gabapentinoid, consider referral to a pain specialist for evaluation of alternative treatment options rather than combining pregabalin and gabapentin 1.